Retosiban also known as GSK-221,149-A is an oral drug which acts as an

oxytocin receptor The oxytocin receptor, also known as OXTR, is a protein which functions as receptor for the hormone and neurotransmitter oxytocin. In humans, the oxytocin receptor is encoded by the ''OXTR'' gene which has been localized to human chromosome 3p25 ...

antagonist An antagonist is a character in a story who is presented as the main enemy or rival of the protagonist and is often depicted as a villain.GlaxoSmithKline GSK plc (an acronym from its former name GlaxoSmithKline plc) is a British Multinational corporation, multinational Pharmaceutics, pharmaceutical and biotechnology company with headquarters in London. It was established in 2000 by a Mergers an ...

for the treatment of

preterm labour Preterm birth, also known as premature birth, is the birth of a baby at fewer than 37 weeks gestational age, as opposed to full-term delivery at approximately 40 weeks. Extreme preterm is less than 28 weeks, very early preterm birth is between ...

. Retosiban has high affinity for the oxytocin receptor (K_i = 0.65 nM) and has greater than 1400-fold selectivity over the related

vasopressin Mammalian vasopressin, also called antidiuretic hormone (ADH), arginine vasopressin (AVP) or argipressin, is a hormone synthesized from the ''AVP'' gene as a peptide prohormone in neurons in the hypothalamus, and is converted to AVP. It ...

receptors

Mechanism of action

Retosiban is a competitive oxytocin receptor antagonist which blocks the oxytocin-mediated contraction of the uterine smooth muscle in the female uterus that occurs during the initiation of preterm labour. This has been used to prevent preterm labour and

premature birth Preterm birth, also known as premature birth, is the birth of a baby at fewer than 37 weeks gestational age, as opposed to full-term delivery at approximately 40 weeks. Extreme preterm is less than 28 weeks, very early preterm birth is betwee ...

Pharmacology

Retosiban has been shown to be an effective

tocolytic Tocolytics (also called anti-contraction medications or labor suppressants) are medications used to suppress premature labor (from Greek τόκος ''tókos'', "childbirth", and λύσις ''lúsis'', "loosening"). Preterm birth accounts for 70% ...

. By intravenous and oral administration it produces a dose-dependent decrease in oxytocin-induced uterine contractions in non-pregnant female rats. In late-term pregnant rats it significantly reduces spontaneous uterine contractions in a dose-dependent manner by intravenous administration. In humans retosiban prolongs pregnancy and reduces preterm birth. Intravenous administration of retosiban in women with spontaneous preterm labour was associated with a greater than 1-week increase in time to delivery compared with placebo, a significant reduction in preterm deliveries, a non-significant increase in uterine quiescence, and a favourable safety profile. The results demonstrate proof-of-concept in the treatment of threatened spontaneous preterm labour

Pharmacokinetics

The oral bioavailability of retosiban is in the order of 100% in the rat with a half life of 1.4 hours. It has low to moderate intrinsic clearance in

microsomes In cell biology, microsomes are heterogeneous vesicle-like artifacts (~20-200 nm diameter) re-formed from pieces of the endoplasmic reticulum (ER) when eukaryotic cells are broken-up in the laboratory; microsomes are not present in healthy, l ...

from three pre-clinical species (rat, dog, cynomolgus monkey) and low intrinsic clearance in human microsomes. It has a good

cytochrome P450 Cytochromes P450 (P450s or CYPs) are a Protein superfamily, superfamily of enzymes containing heme as a cofactor (biochemistry), cofactor that mostly, but not exclusively, function as monooxygenases. However, they are not omnipresent; for examp ...

(Cyp450) profile with no significant inhibition, with IC50 > 100μM, low protein binding (<80%) and low predicted CNS penetration.

Physical and chemical properties

physiological pH Physiology (; ) is the scientific study of functions and mechanisms in a living system. As a subdiscipline of biology, physiology focuses on how organisms, organ systems, individual organs, cells, and biomolecules carry out chemical and ...

, retosiban exists in an uncharged state. It has good solubility (> 0.22 mg/ml), with a

logd In the physical sciences, a partition coefficient (''P'') or distribution coefficient (''D'') is the ratio of concentrations of a compound in a mixture of two immiscible solvents at equilibrium. This ratio is therefore a comparison of the solubi ...

of 2.2.

Retosiban consists of a central 2,5 diketopiperazine ring with an ''R''- indanyl group at the 3 position and an ''R'' (''S''-secButyl) at the 6 position, both ''cis'' to each other, and with a ''R''-2-methyl

oxazole Oxazole is the parent compound for a vast class of heterocyclic compound, heterocyclic aromatic organic compounds. These are azoles with an oxygen and a nitrogen separated by one carbon. Oxazoles are aromatic compounds but less so than the thiaz ...

ring at the 7 position in the acyclic amide attached to the N1-position. Retosiban is the (3''R'', 6''R'', 7''R'')-isomer and is a sub-nanomolar (Ki = 0.65 nM)

antagonist An antagonist is a character in a story who is presented as the main enemy or rival of the protagonist and is often depicted as a villain.indanyl group at position 3 is the best choice in terms of oxytocin receptor antagonist potency, its replacement by phenethyl and benzyl groups led to a progressive weakening of activity. At C-3, a 4-carbon branched alkyl was shown to be preferred with ''R'' (''S''-secButyl) being the best; smaller alkyl groups result in reduced antagonist activity. The 2-methyl oxazole ring at the 7 position gives good aqueous solubility, low protein binding and minimal Cyp450 interaction. This

structure–activity relationship The structure–activity relationship (SAR) is the relationship between the chemical structure of a molecule and its biological activity. This idea was first presented by Alexander Crum Brown and Thomas Richard Fraser at least as early as 1868. Th ...

(SAR) is supported by the crystal structure of the human oxytocin receptor in complex with retosiban, where the lipophilic indanyl substituent penetrates into a deep, mainly hydrophobic crevice at the bottom of the binding pocket, while the oxazol-morpholine amide moiety is closest to the extracellular surface. The oxazole ring is the most solvent-exposed substituent, and the morpholine ring has no direct interactions with the receptor. The 2,5-diketopiperazine core specifically interacts with the receptor through a polar interaction interface.

Synthesis

Retosiban is a cyclic dipeptide or

2,5-diketopiperazine 2,5-Diketopiperazine is an organic compound with the formula (NHCH2C(O))2. The compound features a six-membered ring containing two amide functional group, groups at opposite positions in the ring. It was first compound containing a peptide bo ...

and these are formed by cyclising the corresponding linear dipeptide. In the short lab-scale and highly

stereoselective synthesis Enantioselective synthesis, also called asymmetric synthesis, is a form of chemical synthesis. It is defined by IUPAC as "a chemical reaction (or reaction sequence) in which one or more new elements of chirality are formed in a substrate molecul ...

of Retosiban 8 the linear peptide 5 is formed by the four-component

Ugi reaction In organic chemistry, the Ugi reaction is a multi-component reaction involving a ketone or aldehyde, an amine, an isocyanide and a carboxylic acid to form a bis-amide. The reaction is named after Ivar Karl Ugi, who first reported this reaction in ...

of the

carboxybenzyl Benzyl chloroformate, also known as benzyl chlorocarbonate or Z-chloride, is the benzyl ester of chloroformic acid. It can be also described as the chloride of the benzyloxycarbonyl (Cbz or Z) group. In its pure form it is a water-sensitive oily c ...

(Cbz) protected R-indanylglycine 1, D-alloisoleucine methyl ester hydrochloride 2, 2-methyloxazole-4-carboxaldehyde 3 and 2-benzyloxyphenylisonitrile 4. Hydrogenation to remove the Cbz and benzyl protecting groups, enabled cyclization of the linear peptide 5 to occur to give the phenolic cyclic dipeptide 6. Hydrolysis of the phenolic amide, by reaction with carbonyl diimidazole (CDI), followed addition of aqueous

hydrochloric acid Hydrochloric acid, also known as muriatic acid or spirits of salt, is an aqueous solution of hydrogen chloride (HCl). It is a colorless solution with a distinctive pungency, pungent smell. It is classified as a acid strength, strong acid. It is ...

gave the acid 7 which was converted to the amide Retosiban 8 by activating the acid with the peptide coupling reagent

PyBOP PyBOP (benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate) is a reagent used to prepare amides from carboxylic acids and amines in the context of peptide synthesis. It can be prepared from 1-hydroxybenzotriazole and a chlorophos ...

(benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate) followed by the addition of

morpholine Morpholine is an Organic compound, organic chemical compound having the chemical formula oxygen, O(carbon, Chydrogen, H2CH2)2nitrogen, NH. This heterocycle features both amine and ether functional groups. Because of the amine, morpholine is a bas ...

. Although the linear peptide 5 and the cyclic dipeptide 6 are a mixture of

diastereoisomers In stereochemistry, diastereomers (sometimes called diastereoisomers) are a type of stereoisomer. Diastereomers are defined as non-mirror image, non-identical stereoisomers. Hence, they occur when two or more stereoisomers of a compound have dif ...

(7''RS'') at the exocyclic amide, the hydrochloric acid hydrolysis of the activated phenolic amide caused

epimerisation In stereochemistry, an epimer is one of a pair of diastereomers. The two epimers have opposite configuration at only one stereogenic center out of at least two. All other stereogenic centers in the molecules are the same in each. Epimerization is t ...

at the exocyclic position and yielded the acid 7 with the required (7''R'')-stereochemistry as the major product. Synthesis of Retosiban

References